The number of people with allergic conditions such as pollinosis, atopic dermatitis, and atopic asthma has increased in recent years, and this has become a problem in society. These allergic diseases are classified as type I allergy that is mediated by IgE.
The high-affinity IgE receptor (hereinafter, FcεFI) expressed on the membrane of mast cells and basophils is known to be a key glycoprotein in type I allergic reaction. When antigen-specific IgE bound to FcεFI is crosslinked by its corresponding multivalent antigen (for example, Japan cedar pollen in patients with Japan cedar pollinosis, dust mite antigen in patients with dust mite allergy, etc.), the FcεFI aggregates, signal transduction cascades are initiated, and initial activation of mast cells occurs. The result is an explosive release of various chemical substances that cause allergic inflammation, more specifically, the initial release of histamine that has already been stored in intracellular granules is followed by the new synthesis and release of leukotrienes, prostaglandins, and other intracellular metabolites, manifesting thereby in type I allergic reaction.
Furthermore, synthesis and secretion of cytokines from mast cells are induced by aggregation of FcεFI on the mast cell, and these cytokines induce expression of various adhesion molecules in nearby vascular endothelial cells. Mediated by these adhesion molecules, eosinophils and lymphocytes in the blood bind to vascular endothelial cells at the site of inflammation and accumulate. As a result, a late asthmatic response occurs. Furthermore, the FcεFI expressed in Langerhans cells in the skin is thought to be involved in the pathogenesis of atopic dermatitis through antigen presentation, cytokine production, etc.
Based on the above knowledge, a promising strategy for the development of agents for prevention and treatment of allergic diseases is to target FcεFI, which specifically mediates type I allergy, and to interrupt signal transduction from this receptor at its source.
In humans the FcεFI protein is expressed on the cell surface and functions either as a tetramer consisting of an α-chain, β-chain, and two γ-chains, or a trimer consisting of an α-chain and two γ-chains. The α-chain binds directly to IgE through its extracellular domain, while the β-chain and γ-chains are involved in intracellular signal transduction. Among these subunits, the β-chain not only plays an important role in amplifying the signal mediated by the γ-chains (see, for example, non-patent documents 1 and 2), but recently it has been reported that the β-chain enhances the expression of cell surface FcεFI by promoting the maturation of the α-chain (see, for example, non-patent document 3). This means that the inhibition of β-chain expression will reduce the expression of these receptors on the cell surface and attenuate the intensity of the intracellular signal that is transduced by each individual receptor. It is expected that inhibition of the expression of this β-chain can control allergic reaction very effectively.
Specific repression of transcription of the β-chain gene is a useful method for inhibiting expression of the FcεFI β-chain.
The genomic structure and nucleotide sequence of the human FcεFI β-chain gene have already been determined (see, for example, non-patent document 4). However, analysis has been performed only on the region upstream of the start codon that contains the promoter region, and it has been reported that a region containing an Oct-1 binding motif is essential for promoter activity (see non-patent document 5).
However, a transcription regulatory region has not been specifically identified in another region of the gene, and because there are many instances in which a transcription regulatory region is present in an intron or an untranslated region on the 3′ side of a gene, it is possible that a region that regulates transcription of the FcεFI β-chain gene is present in a region of the gene that has not yet been analyzed.    [Non-patent document 1]    S. Lin et al., Cell 85, 985-995 (1996)    [Non-patent document 2]    D. Domobrowicz et al., Immunity 8, 517-529 (1998)    [Non-patent document 3]    E. Donnadieu et al., Immunity 12, 515-523 (2000)    [Non-patent document 4]    H. Kuster et al., J. Biol. Chem. 267, 12782-12787 (1992)    [Non-patent document 5]    Y. Akizawa et al., Int. Immunol. 15, 549-556 (2003)